18 th Meeting of FDA TSE Advisory Committee: 31 October 2005 Summary FDA Blood Products Advisory...
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Transcript of 18 th Meeting of FDA TSE Advisory Committee: 31 October 2005 Summary FDA Blood Products Advisory...
18th Meeting of FDA TSE Advisory Committee:
31 October 2005Summary
FDA Blood Products Advisory Committee85th Meeting
03 November 2005Holiday Inn
Gaithersburg MD
David M. Asher, MD<[email protected]>
Laboratory of Bacterial, Parasitic and Unconventional Agents
Division of Emerging & Transfusion-Transmitted Diseases
Office of Blood Research & ReviewCenter for Biologics Evaluation & Research
US Food & Drug Administration
18th FDA TSEAC Agenda
1. BSE worldwide and USA: USDA update
2. TSE decontamination of surgical devices: CDRH update
3. CBER decisional issue 1. Advice on further development of FDA risk assessment for vCJD and plasma-derived factor VIII
4. CBER decisional issue 2. Validation criteria and possible label claims for devices to remove TSE infectivity from blood components
Recipients surviving >3yrs post transfusion of blood components from vCJD/CJD Donors
(using data from UK TMER and US ARC look-back studies,S. Anderson, FDA TSEAC 14 Oct 2004)
Fisher's Exact Test comparing rates of infection after transfusions from vCJD and CJD donors suggests a statistically significant difference between the two groups (1.2% likelihood that the difference occurred by chance). Risk of transfusion-transmitted vCJD >> sporadic CJD
InfectionNo
Infection
CJD 0 116
vCJD 2 13
vCJD : Non-UK = 27cases(October 2005 UK =158) from R. Knight/CJD SU Edinburgh
FRANCE 15
ITALY 1
NETHERLANDS 1
PORTUGAL 1
SPAIN1
REPUBLIC of IRELAND 2
REPUBLIC of IRELAND 2 USA 1 CANADA 1 JAPAN1
SAUDI ARABIA (source uncertain) 1
Probably acquired in UK Probably non-UK
Donor travel history UK, FR, EuropeAdjustments for duration & year traveled, donor age Screening questionnaire
Plasma pool sizeQuantity of vCJD agent in poolReduction of vCJD agent during manufacture
Percent contaminated vialsAmount vCJD agent per FVIII vialAnnual dose Factor VIII
Module 1vCJD
Prevalence in UK
Module 2vCJD
Prevalence in US Donors
Module 3FVIII
Processing
Module 4Utilization of FVIII
INPUT MODULE OUTPUT
Number US vCJD donorsNumber vCJD donors post-screeningTotal number vCJD donations
Percentage plasma pools / vials with vCJD agentQuantity vCJD agent per FVIII vial
Annual exposure of FVIII recipients to vCJD agent
Estimate of vCJD prevalence in United Kingdom
UK surveillance dataPredictive modeling based on UK vCJD cases
Critical elements of vCJD risk assessment:
Prevalence of vCJD in US Plasma
UK vCJD prevalence US donor travel history Time of travel relative to UK BSE prevalence Travel: Source Plasma vs recovered plasma
donors Risk reduction by donor deferral Effectiveness of donor deferral Residual risk: non-deferred (short-duration)
travelers
Module 1 Prevalence of vCJD in United
Kingdom
Proposed Modeling Approaches
Two sources of UK vCJD prevalence data:
1. Predictive models based on UK vCJD cases2. Surveillance data based on examination of
appendix samples
Problem:Disparity ~ 10 to 100 fold between approaches
Module 1Prevalence of vCJD in UK
Predictive models based on observed cases of vCJD and “back calculation”
method______________________________________________
(1) Ghani et al 2003 vCJD estimated median 100 cases (10
to 2,600 - 95% CI) Median 1 in 500,000
(2) Boelle et al 2003 vCJD UK estimated cases: 183 to 304
(3) Llewelyn et al 2004 vCJD UK est 1 in 15,000 to 1 in 30,000
or 1,000-2,000 infections
Unique Pathology of vCJD (Chazot G & al. Lancet 1996;347:1181. Will RG & al. Lancet
1996:347:921-5. Hill AF & al. Lancet 1999;353:183-9)
Module 1 Prevalence of vCJD in UK
Empirical appendix surveillance data (Hilton et al. 2004)
3 PrPres-positive samples in 12,674 samples tested ~ mean of 1 positive in 4,225 individuals
(mostly 20- to 30-yr-old patients)Approximately 13,000 vCJD infected UK
individuals in UKData should be further age-adjusted using
reported UK vCJD case age profileDoes not consider infected persons before
appendix becomes positive for PrPres (e.g., last transfusion-transmitted infection in a PRNP-codon-129 met/val person)
Issue 1. Advice on Assumptions for vCJD
FVIII Risk Assessment
UK Prevalence: Use empirical prevalence value based on UK PrPres tissue survey allowing for a pre-clinical/sub-clinical infectious state in donors of all PRNP-codon-129 genotypes
Issue 1. Advice on Assumptions for vCJD
FVIII Risk Assessment
Screening sensitivity for vCJD risk: Advised against using estimates from analogous donor screening situations (showing 90-99% sensitivity of screening) and recommended instead 85% most likely
Source Plasma donor information: Encouraged obtaining survey data for travel by apheresis donors rather than extrapolating from a travel survey for donors of Whole Blood
Levels of vCJD infectivity in human plasmaWhat infectivity range (in ID50/ml) should FDA select for human blood/plasma based on studies in animals?
During what part of the incubation period?
FDA proposed a triangular distribution:
Minimum = 0.1 Most likely = 10 Maximum = 310
FDA proposed assuming infectivity to be potentially present in blood throughout the entire incubation period.
From Dr RG Rohwer, Baltimore VAH
InfectedExperimental TSEs: infectivity in blood
|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|| | | | | | | | | | | | | 1 8 16 27 41 51 60 70 80 90 100 120
|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|_0 1 2 3 4 5 6 7 8 9 10 15 20 25 30 35 __|___|___|___|___|___| 42
Weeks Clinical disease
? ?
Uninfected
Days Clinical disease
scrapie in mouse
scrapie in hamster
Eklund/5x107im/30 ul blood clot ic30 ul serum ic2 exp. same result
|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|0 5 10 20 30 40 50 120
Days Clinical disease
scrapie in hamsterDiringer/ 106 ip200 ul blood equiv ic
Cassacia/ 106 ip200 ul blood equiv ic
(214)(151) (151) (186) (191)
(108)(116) (114) (113) (128) (124) (131) (121) (132) (138)
Numbers in parentheses are mean incubation times.
file: Viremia6.pptRobert G. Rohwer, Ph.D.
|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|0 1 2 3 4 5 6 7 8 9 10 15 20 25
CJD in guinea pigManuelidis/ic inoc .1ml clinical/0.1ml buffy coat ic, ip, sc, im
|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___0 1 2 3 4 5 6 7 8 9 10 15
Clinical diseaseWeeks
GSS (fCJD) in mouseKuroda/3x104ic inoc30 ul buffy coat ic &100 ul serum ip/ 100ul rc ip
(281) (213) (156) (142)
Weeks Clinical disease
(443) (463)
(429)(308)(448) (504)(379)
(396)(210)(343)
(184)(307)
(147)
(447)
Infectivity in blood of terminally ill mice inoculated with mouse-adapted
GSS (Fu-1) agent(Brown P et al. Transfusion 1999;39:1169-78)
Infectivity in ic IU/ml
Expt 1 Expt 2
Pool 1
Expt 2
Pool 2
Buffy coat 44 NT 106
Plasma 10 34 22
Titers of scrapie-infected hamster blood
from clinically ill animalsIn
fect
iou
s D
oses
/ml
Titer of TSE Infectivity in Blood of Clinically Affected Animals
ID/m
l
0
5
10
15
20
25
Infe
ctio
us
Dos
es/m
l
Splenectomies
Individual
Pools
meanmedian
From Dr RG Rohwer, Baltimore VAH
Titer in ID/ml of Preclinical Hamster Blood
Days after Inoculation
0 20 40 60 80 100 120 140 160
Infe
cti
ou
s D
os
es
/ml
0
1
2
3
4
5
6
7
Cli
nic
al
Dis
ea
se
Infe
cti
ou
s D
os
e/U
nit
450
2700
90
2250
1800
1350
900
3150
0
From Dr RG Rohwer, Baltimore VAH
Issue 1. Advice on Assumptions for vCJD
FVIII Risk Assessment
Infectivity level: Agreed that—based on rodent data—10 ID50/ml blood most likely and minimum of 0.1 ID50 prudent, but offered mixed advice on upper level (100 to 1000 ID50 mentioned)
Duration of infectivity in blood relative to incubation period: Agreed compromise advice estimating infectivity in last 50% of incubation period, modified if shown to be a critical parameter in sensitivity analysis
Issue 1. Advice on Assumptions for vCJD
FVIII Risk Assessment
Pool size: Agreed with FDA-proposed “bimodal” distribution with pools of 20,000 and 60,000 donations considered most likely
Clearance of TSE infectivity by manufacturing processes: Agreed with FDA proposal to use three different ranges for various products
Issue 1. Plasma fractionation:FDA proposes 3 ranges of estimated vCJD infectivity
clearance by manufacturing Range of reduction
(log10)Process
Likely minimum
2-3 Single step with moderate clearance
Mid-range 4-6 Single step with higher clearance or Multiple additive steps
Likely maximum
7-9 Multiple additive steps
Issue 1. Advice on Assumptions for vCJD
FVIII Risk Assessment Clinical use: Agreed with FDA that CDC
databases for FVIII use (1993-98 survey of all HA pts in 6 states and Universal Data Collection Program [UCD]) were best available (but not enough—especially for von Willebrand’s disease)
Additional information needed: Agreed with FDA proposal to extrapolate from existing data to estimate use by year and use patient-based medical record data if needed to resolve inconsistencies
Issue 1. Advice on Assumptions for vCJD
FVIII Risk Assessment Cumulative risk from repeated exposures to
“sub-infectious” doses: Agreed with FDA that experimental studies showing infection following frequent exposures of rodents to amounts of infectivity not infectious by single exposures or repeated at long intervals are a concern
Risk per annum: Agreed with FDA proposal to estimate vCJD risk per annum rather than per dose (but did not advise other modification to the risk model)
Issue 1. Advice on Assumptions for vCJD
FVIII Risk Assessment
Special concern: risk communicationRisk of transmission by plasma
derivatives is theoretical. (Even in UK, no case of vCJD has been recognized in a recipient of a plasma derivative.)
Especially difficult to communicate highly uncertain theoretical risks
Notification might cause adverse effects Patient anxiety Health care provider anxiety Other
Participation of patient groups helpful
TSEAC Decisional Issue 2.Validation criteria and possible
label claims for devices to remove TSE infectivity
from blood components UK regulatory authorities plan an
independent evaluation of CE-marked blood filters purported to reduce TSE infectivity: Expect minimal 3 log10 reduction of spiked
infectivity (demo by Western blot and bioassay) at ambient temp and 4oC
Component (RBC) must maintain functionality at expiry by usual tests
Seek “surrogate” markers suitable for QA Three manufacturers described 3
promising devices for clearing TSE agents (one CE-marked)
TSEAC Decisional Issue 2.Validation criteria and possible
label claims for devices to remove TSE infectivity
from blood components TSEAC suggested modifications to FDA’s
proposed criteria: 3 log10 reduction of spiked infectivity
(demonstrated by Western blot and bioassay)
Remove all detectable infectivity from endogenously infected animal blood
2 animal models and 2 strains of TSE agent 1 agent strain derived from cow with BSE
or human with vCJD (rodent-adapted) Filtered blood components should maintain
functionality at expiry by usual tests
TSEAC Decisional Issue 2.Validation criteria and possible
label claims for devices to remove TSE infectivity
from blood components TSEAC suggested modifications to
FDA’s proposed criteria for validation (continued): Desirable to demonstrate that device
removes all detectable endogenous TSE infectivity from whole units of blood of large animals (sheep scrapie/BSE; ?? primates—not yet available)
Since bioassays for residual infectivity by transfusing of animals of the same species, while ideal, are generally not feasible, may test in susceptible transgenic mice (although sensitivity relative to large animals not known)
TSEAC Decisional Issue 2.Validation criteria and possible
label claims for devices to remove TSE infectivity
from blood components TSEAC suggested modifications to FDA’s
proposed criteria for validation (continued): While reproducibility of results at
separate study sites is desirable, it may be difficult to arrange for two labs with required equipment and TSE expertise
Study should be large enough for statistical validity
Studies described might support label claims for reduction of TSE infectivity (small animal models), ?? prevention of transfusion-transmitted TSE (only after large animal study)